PROJECT SUMMARY/ABSTRACT In advanced vaso-occlusive disease, restoration of blood flow to the distal tissue bed is essential for limb and life salvage. Methods of revascularization include angioplasty and stenting for focal disease but bypass surgery is required for more extensive occlusions. The ideal vascular conduit is autologous vein but this is often depleted or of poor quality. The alternative prosthetic grafts exhibit relatively poor patency in bypasses to distal targets, failing due to acute thrombosis. Graft modification with heparin bonding has not made much impact. In preliminary studies, native arteries have been demonstrated to possess a wrinkled luminal topography at relaxed states that flattens as the arteries distend under pressure. While the function of this dynamic luminal topography in normal arteries has not yet been studied, the incorporation of a similar dynamic topography onto synthetic surfaces significantly reduced platelet accumulation. Based on these findings, we hypothesize that dynamic luminal topography may represent an innate arterial mechanism to prevent platelet adhesion and thrombus formation and building this topography into prosthetic vascular grafts can improve graft patency. This hypothesis will be addressed in this proposal through the following Specific Aims: 1). Evaluate arterial topography under physiologic and pathophysiologic conditions and its effect on platelet adhesion and surface biofouling; and 2). Engineer dynamic topography into prosthetic vascular grafts to improve resistance to platelet adhesion and thrombosis. Through a multidisciplinary team of investigators from Departments of Surgery, Chemical Engineering, Mechanical Engineering, and Cell Biology, we will conduct experiments to evaluate the function of dynamic topography in native arteries as it relates to vascular homeostasis and the impact of disease states such as hypertension and atherosclerosis on this function. We will also fabricate vascular grafts that mimic this arterial property and test its function as a bypass graft in large animal studies. Completion of these studies will have a significant impact on better understanding the contribution of arterial biomechanics to vascular homeostasis and on disease pathogenesis. The creation of a prosthetic graft with improved resistance to platelets and thrombosis based on mechanical properties will greatly impact the treatment and outcomes of patients with vaso-occlusive disease. If successful, the translation of this technology to clinical use will be much more streamlined and less costly than for technology based on tissue engineered grafts. Dynamic topography technology may also have far reaching applications to other medical and nonmedical devices that are troubled with soiling at interfaces such as artificial heart and valves, hemodialysis circuits, and water filtration systems.